Benzoheterocyclicalkyl derivatives of 1-phenyl-1,3,8, triazaspiro (4,5) decan-4-one

ABSTRACT

Benzoheterocyclic-alkyl derivatives of 1-phenyl-1,3,8triazaspiro(4,5)decan-4-one in which the benzoheterocyclic moiety is thianaphthenyl or benzofuranyl, optionally substituted by chloro, bromo, fluoro, methyl, methoxy or trifluoromethyl, have neuroleptic activity. The compounds are generally prepared from either the benzo-heterocyclicalkyl halide by reaction with the appropriate amine or the benzoheterocyclic amine by condensation with a 5,5-bis ( Beta -haloethyl) barbituric acid.

United States Patent Kaiser et al.

BENZOHETEROCYCLICALKYL DERIVATIVES OF l-PHENYL-l,3,8, TRIAZASPIRO (4,5) DECAN-4-ONE Inventors: Carl Kaiser, Haddon Heights, N.J.;

Charles L. Zirkle, Philadelphia, Pa.

Smith Kline & French Laboratories, Philadelphia, Pa.

Filed: Mar. 11, 1971 Appl. No.: 123,442

Assignee:

Related US. Application Data Division of Ser. No. 771,320, Oct. 28, 1968, Pat. No. 3,629,267.

US. Cl...260/293.57, 260/293.58, 260/294.8 C, 260/295 LB, 260/3305, 260/3462 R, 260/999 Int. Cl. ..C07d 63/18 Field of Search ..260/293.57, 293.58

[56] References Cited UNITED STATES PATENTS 3,476,760 ll/l969 Kaiser et al "260/2934 Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas Todd Attorney-Richard D. Foggio et a].

[57] ABSTRACT Benzoheterocyclic-alkyl derivatives of l-phenyl-l,3,8- triazaspiro[4,5ldecan-4-one in which the benzoheterocyclic moiety is thianaphthenyl or benzofuranyl, optionally substituted by chloro, bromo, fluoro, methyl, methoxy or trifluoromethyl, have neuroleptic activity. The compounds are generally prepared from either the benzo-heterocyclicalkyl halide by reaction with the appropriate amine or the benzoheterocyclic amine by condensation with a 5,5 bis (B-haloethyl) barbituric acid.

5 Claims, No Drawings BENZOHETEROCYCLICALKYL DERIVATIVES F l-PHENYL-l ,3,8, TRIAZASPIRO (4,5) DECAN-4- ONE This application is a division of application Ser. No. 771,320 filed on Oct. 28, 1968 now US. Pat. No. 3,629,267.

This invention relates to novel benzoheterocyclicalkyl derivatives of 4-(2-keto-l-benzimidazolinyhpiperidine, 4-( Z-ketol -benzimidazolinyl 1 ,2,3,6- tetrahydropyridine, l-phenyll ,3,8-triazaspiro[ 4,5]decan-4-one and 2,4,9-triaza-spiro[5,5lundecan- 1,3,5-trione. These compounds have useful pharmacodynamic activity and more specifically have neuroleptic activity as demonstrated in standard animal pharmacological test procedures. Exemplary of the activity of the compounds of this invention is the moderate to marked decreased motor activity, catalepsy, hypotonia and ptosis produced in rats upon oral administration of doses ranging from 1.0 to 50.0 mg/kg. At these does no toxicity is observed.

The compounds of this invention are represented by the following general structural formula:

Preferred compounds include those of formula I wherein R is in the or fi-position, Y is sulfur, n is 3 and the benzoheterocyclic moiety is 3-substituted.

The compounds of this invention may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known to the art, are formed with both inorganic or organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicyclic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic,glutamic, benzenesulfonic, hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The compounds of this invention wherein Z is 4-(2- ketol -benzimidazolinyl l -piperidyl 4-( 2-ketol benzimida-zolinyl l ,2, 3 ,6-tetrahydrol -pyridyl or 1- phenyl-l ,3,8-triazaspiro[4,5 ldec-8-yl-4-one are generally prepared from a benzoheterocyclicalkyl halide having the formula:

Formula II wherein R1, Y and n are as defined for formula 1 and X is halogen, preferably chlorine or bromine, by reaction with the appropriate amine (H2). The halides of formula H are prepared from corresponding alkanoic acids (n is l to 3) via reduction with lithium aluminum hydride to the alcohol followed by reaction with a phosphorus trihalide, such as phosphorus tribromide, to give the alkyl halide. The required alkanoic acids are obtained as described in Belgian Patent No. 7] l,675.

The compounds of formula I wherein Z is 2,4,9- triaza-spirol 5,5 ]undec-9-yll ,3 ,S-dione are generally prepared from a benzoheterocyclicalkyl amine having the formula:

4+ IZ)u Formula I wherein R,, Y and n are as defined in formula I by reaction with a 5,5-bis(B-haloethyl)-barbituric acid derivative, the halo group being iodo or bromo. The amines of formula [I] are prepared from corresponding alkanoic acids (n is l to 3) via reacting the acid with thionyl chloride to give the acid chloride which is treated with ammonia and reducing the resulting amide with lithium aluminum hydride to yield the alkyl amine.

The compounds of this invention may be administered orally or parenterally in conventional dosage unit fonns such as tablets, capsules, injectables or the like, by incorporating the appropriate dose of a compound of formula 1, either as the free base or an acid addition salt thereof, with carriers according to accept pharmaceutical practices.

The foregoing is a general description of how to prepare the compounds of this invention. The following examples illustrate the preparation of specific compounds having neuroleptic activity. However this should not be construed as limiting the scope of the invention since appropriate variations in the starting materials will produce other products set forth hereinabove.

PREPARATIONS A. 3-( 3-Thianaphthenyl)-propyl bromide (Formula 11) To a mixture of 4.0 g. (0.105 m.) of lithium aluminum hydride in 1,000 ml. of dry ether is added a solution of 10.7 g. (0.052 m.) of 3-( 3-thianaphthenyl)- propionic acid in 50 ml. of dry tetrahydrofuran, dropwise with stirring. The resulting mixture is stirred and refluxed for 4 hours, decomposed and filtered. The dried filtrate is evaporated in vacuo and the residue distilled to give 3-(3-thianaphthenyl)-propanol, b.p. 1 33-158 C./0.5 mm.

A solution of 9.2 g. (0.0479 In.) of 3-(3-thianaphthenyl)-propanol in 250 ml. of dry ether is stirred while ml. of phosphorus tribromide in 50 ml. of dry ether is added dropwise. The resulting mixture is stirred and refluxed for 1 hour, poured into ice-water and the layers separated. The ether layer is washed, dried and evaporated in vacuo to give an oil which is distilled to give 3-(3-thianaphthenyl)-propyl bromide b.p. 147- 190 C./0.l mm.

B. 3-( 3-Thianaphthenyl)-propyl amine (Formula 111) A mixture of 5.2 g. (0.025 m.) of 3-(3-thianaphthenyl)-propionic acid and ml. (0.025 m.) of thionyl chloride is allowed to stand at room temperature overnight, diluted with benzene and evaporated in vacuo to give the acid chloride. The latter is dissolved in ether and treated with an excess of aqueous ammonia. The resulting mixture is refluxed for 1 hour and the separated organic layer is washed, dried and concentrated to give 3-(3-thianaphtheny1)-propionamide. The amide is reduced with an equimolar amount of lithium aluminum hydride in dry ether to yield 3-( 3-thianaphthenyl)-propylamine.

Following the procedures of parts A or B above, other il -substituted thianaphthene-or benzofuranab kanoic acids are similarly converted to corresponding alkyl bromides or amines.

EXAMPLE 1 A mixture of 4.7 g. (0.0219 in.) of 4-(2-keto-lbenzimidazo1iny|)-1,2,3,6-tetrahydropyridine, 8.0 g. (0.0314 In.) of 3-(3-thianaphthenyl)-propyl bromide, 1.84 g. (0.0219 m.) ofsodium bicarbonate and 0.3 g. of potassium iodide in 500 ml. of dry toluene is stirred and refluxed for 4 days. The reaction mixture is evaporated in vacuo and the residue is dissolved in chloroform/water. The water layer is washed with chloroform and the total chloroform solution is washed with dilute hydrochloride acid, dried and evaporated in vacuo to give l-[3-(3-thianaphthenyl)-propyl]-4-( 2- keto- 1 -benzimida-zonlinyl )-1 ,2,3 ,6- tetrahydropyridine; hydrochloride m.p. 252254 C.

Similarly, by employing 3-(5-chloro-2-thianaphtheny| )-propyl bromide (obtained from the propionic acid) in the above reaction there is produced 1-[3-(5- chloro-2-thianaphthenyl )-propyl -4-( 2-keto-l benzimidazolinyl 1 ,2,3 ,6-tetrahydropyridine.

EXAMPLE 2 A mixture of 8.0 g. (0.0314 m.) of 3-(3-thianaphthenyl)-propyl bromide, 4.4 g. (0.0203 m.) of 4-(2-keto-lbenzimidazo-linyl)-piperidine, 1.71 g. (0.0203 m.) of sodium bicarbonate and 0.3 g. of potassium iodide in 500 ml. of dry toluene is stirred and refluxed for 4 days.

The reaction mixture is evaporated in vacuo and the residue dissolved in chloroform/water. The layers are separated and further worked up as in Example 1 to yield 1 [3-( 3-thianaphthenyl)-propyl ]-4-( 2-ketol benzimidazolinyl)-piperidine; hydrochloride m.p. 287-294 C.

Similarly, by employing an equivalent amount of 3- (5-methyl-3-thianaphthenyl)-propyl bromide (obtained from the propionic acid) as described above there is prepared l-[3-(5-methy1-3-thianaphthenyl)- propyl ]-4-( 2-ketol -benzimidazo-linyl )-piperidine.

EXAMPLE 3 Following the procedures of Example 1, a mixture of 5.0 g. (0.0216 m.) of 1-phenyl-l,3,8-triazaspiro[ 4,5]decan-4-one, 8.0 g. (0.0314 m.) of 3-(3-thianaphthenyl)-propyl bromide, 1.82 g. (0.0216 m.) of sodium bicarbonate and 0.3 g. of potassium iodide in 500 ml. of dry toluene is stirred and refluxed for 4 days, then filtered while hot. The filtrate is evaporated in vacuo and the residue worked up to give 1-pheny1-8-[3- (3-thianaphthenyl)-propyl] 1 ,3,8-tria7aspiro [4,5 decan-4-one; hydrochloride m.p. 258-260 C.

Use of 3-( 6-methoxy-2-thianaphthenyl)-propyl bromide (obtained from the propionic acid) as the reactant above yields l-phenyl-8-[3-(6-methoxy-2-thianaphthenyl )-propyl 1 ,3 ,8-triazaspiro [4,5 ]decan-4- one.

EXANEPLE 4 A solution of 6.0 g. (0.03 m.) of 3-(3-thianaph-thenyl)-propylamine in ml. of anhydrous ethanol is added to a suspension of 11.7 g. (0.027 m.) of 5,5- bis(B-iodoethyl) barbituric acid in m1. of anhydrous ethanol and the mixture is shaken two and one-half hours in the dark under nitrogen. One equivalent of dry silver oxide and, after shaking for three days, one more equivalent of silver oxide is added. The mixture is then shaken for 3 hours, briefly heated to 60 C., filtered and evaporated. The residue is purified by chromatography to give 9-[ 3-( 3-thianaphthenyl )-propyl }-2 ,4 ,9- triazaspiro[ 5 ,Sundecan-I 3 ,5 -trione.

Similarly, by reacting 3-( 3-benzofuranyl)-propylamine (obtained from the propionic acid) with 5,5- bis(B-iodoethyl)barbituric acid as described above there is prepared 9[3-(3-benzofurany1)-propyl]-2,4,9- triazaspiro[ 5 ,Sundecan- 1 ,3 ,5-trione.

EXAMPLE 5 Following the procedure of Example 1, an equivalent amount of 3-(2-benzofuranyl)-propyl bromide (obtained from the propionic acid) is reacted with 4-(2- ketol -benzimidazo-linyl )-l ,2, 3 ,6-tetrahydropyridine in the presence of sodium bicarbonate and potassium iodide to yield upon workup l-[3-(2-benzofuranyl)- propyll-4-(2-keto-1-benzimidazolinyl)-l ,2,3 ,6- tetrahydropyridine.

By employing instead 3-(3-benzofuranyl)-propyl bromide as the reactant above there is obtained 1-[3- 3-benzo-furanyl)-propyl]-4-(2-keto-1 -benzimidazo|inyl )-1 ,2,3 ,6-tetrahydropyridine.

EXAMPLE 6 Following the procedure of Example 1, 3-(6-fluoro- 3-thianaphthenyl)-propyl bromide (obtained from the propionic acid) is reacted with 4-(2-keto-1- benzimidazolinyl)-1,2,3,6-tetrahydropyridine to give 1- [3-( 6-fluoro-3-th1'anaphthenyl )-propyl ]-4-( 2-ketol benzimidazolinyl 1 ,2,3 ,6-tetrahydropyridine.

Use of 3-(G-trifluoromethyl-3-thianaphthenyl)- propyl bromide as described above yields l-[3-(6- trifluoromethyl-S-thianaphthenyl )-propyl ]-4-( 2-keto-l -benzimidazolinyl )-l ,2 ,3 ,6-tetrahydropyridine.

EXAMPLE 7 Following the procedure of Example I, 3-( 6-bromo- 3-benzofuranyl)-propyl bromide (obtained from the propionic acid) is reacted with 4-(2-keto-lbenzimidazolinyl )-1 ,2,3 ,-tetrahydropyridine to yield the product l-[ 3-(6-bromo-3-benzofuranyl)-propyl]-4- 2keto- 1-benzimidazolinyl)- l ,2 ,3 ,6- tetrahydropyridine.

EXAMPLE 8 or a pharmaceutically acceptable acid addition salt thereof, wherein:

R, is hydrogen, chloro, bromo, fiuoro, methyl,

methoxy or trifluoromethyl; Y is oxygen or sulfur; nisawhole integer from2to 4;and Zis U Nn 2. A chemical compound according to claim 1 in which the benzoheterocyclic moiety is 3-substituted and has the R, substituent in the 5 or (a-position.

3. A chemical compound according to claim 2 in which Y is sulfur and n is 3.

4. A chemical compound according to claim 3 in which R is hydrogen, chloro or fluro.

5. A chemical compound according to claim 4 in which R is hydrogen, being the compound l-phenyl-S- [3-( 3-thianaph-thenyl )-propyl 1,3 ,8-triazaspiro[ 4 ,5 ]decan-4-one. 

2. A chemical compound according to claim 1 in which the benzoheterocyclic moiety is 3-substituted and has the R1 substituent in the 5 or 6-position.
 3. A chemical compound according to claim 2 in which Y is sulfur and n is
 3. 4. A chemical compound according to claim 3 in which R1 is hydrogen, chloro or fluro.
 5. A chemical compound according to claim 4 in which R1 is hydrogen, being the compound 1-phenyl-8-(3-(3-thianaph-thenyl)-propyl)-1,3,8-triazaspiro(4,5)decan-4-one. 